The phylogenetically conserved nuclear factor I (NFI) gene family encodes site-specific transcription factors essential for the development of a number of organ systems. We showed previously that Nfia-deficient mice exhibit agenesis of the corpus callosum and other forebrain defects, whereas Nfic-deficient mice have agenesis of molar tooth roots and severe incisor defects. Here we show that Nfib-deficient mice possess unique defects in lung maturation and exhibit callosal agenesis and forebrain defects that are similar to, but more severe than, those seen in Nfia-deficient animals. In addition, loss of Nfib results in defects in basilar pons formation and hippocampus development that are not seen in Nfia-deficient mice. Heterozygous Nfib-deficient animals also exhibit callosal agenesis and delayed lung maturation, indicating haploinsufficiency at the Nfib locus. The similarity in brain defects in Nfia-and Nfib-deficient animals suggests that these two genes may cooperate in late fetal forebrain development, while Nfib is essential for late fetal lung maturation and development of the pons.Nuclear factor I (NFI) transcription and replication proteins function both in adenoviral DNA replication (12,43,44) and in the regulation of transcription throughout development (21). There are four NFI genes in mammals (Nfia, Nfib, Nfic, and Nfix) and single NFI genes in Drosophila melanogaster, Caenorhabditis elegans, Anopheles spp., and other simple animals (21,30,50). No NFI genes have been found in plants, bacteria, or single-cell eukaryotes. In mammals, NFI proteins function as homo-or heterodimers and are expressed in complex, overlapping patterns during embryogenesis (6, 31). NFI proteins bind to a dyad-symmetric binding site (TTGGCN 5 GCCAA) with high affinity (20,40), and NFI proteins have been shown to either activate or repress gene expression depending on the promoter and cellular context (21, 42). The presence of four NFI genes in mammals with possibly overlapping functions makes it a challenge to identify in vivo targets of individual NFI proteins and the roles of NFI genes in development.We showed previously that disruption of Nfia causes late gestation neuroanatomical defects, including agenesis of the corpus callosum, size reductions in other forebrain commissures, and loss of specific midline glial populations (11, 56). In contrast, disruption of Nfic results in early postnatal defects in tooth formation, including the loss of molar roots and aberrant incisor development (61). In a previous study, insertion of a lacZ reporter gene into the Nfib locus resulted in defects in lung maturation but no apparent defects in brain development (22). Here we report the replacement of the essential exon 2 of the Nfib gene with a lacZ reporter gene and show that mice homozygous for our replacement mutation have major neuroanatomical defects similar to, but more severe than, those of Nfia Ϫ/Ϫ mice. These defects include callosal agenesis, aberrant hippocampus and pons formation, and loss of specific midline glial populatio...

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Inherited mitochondrial respiratory chain disorders are progressive, life-threatening conditions for which there are limited supportive treatment options and no approved drugs. Because of this unmet medical need, as well as the implication of mitochondrial dysfunction as a contributor to more common age-related and neurodegenerative disorders, mitochondrial diseases represent an important therapeutic target. Thirteen children and one adult with genetically-confirmed mitochondrial disease (polymerase γ deficiency, n=4; Leigh syndrome, n=4; MELAS, n=3; mtDNA deletion syndrome, n=2; Friedreich ataxia, n=1) at risk for progressing to end-of-life care within 90 days were treated with EPI-743, a novel para-benzoquinone therapeutic, in a subject controlled, open-label study. Serial measures of safety and efficacy were obtained that included biochemical, neurological, quality-of-life, and brain redox assessments using technetium-99m-hexamethylpropyleneamine oxime (HMPAO) single photon emission computed tomography (SPECT) radionuclide imaging. Twelve patients treated with EPI-743 have survived; one polymerase γ deficiency patient died after developing pneumonia and one patient with Surf-1 deficiency died after completion of the protocol. Of the 12 survivors, 11 demonstrated clinical improvement, with 3 showing partial relapse, and 10 of the survivors also had an improvement in quality-of-life scores at the end of the 13-week emergency treatment protocol. HMPAO SPECT scans correlated with clinical response; increased regional and whole brain HMPAO uptake was noted in the clinical responders and the one subject who did not respond clinically had decreased regional and whole brain HMPAO uptake. EPI-743 has modified disease progression in >90% of patients in this open-label study as assessed by clinical, quality-of-life, and non-invasive brain imaging parameters. Data obtained herein suggest that EPI-743 may represent a new drug for the treatment of inherited mitochondrial respiratory chain disorders. Prospective controlled trials will be undertaken to substantiate these initial promising observations. Furthermore, HMPAO SPECT imaging may be a valuable tool for the detection of central nervous system redox defects and for monitoring response to treatments directed at modulating abnormal redox.

The ketogenic diet was developed in the 1920s as a treatment for intractable childhood seizures when few antiepileptic drugs (AEDs) were available. There are still children whose seizures are refractory even to modern therapy, but use of the ketogenic diet appears to be waning. At Johns Hopkins, we continue to believe that the diet is very effective and well accepted by patients and families. To reevaluate our opinion of the efficacy and acceptability of this form of therapy in patients cared for in the 1980s with the newer AEDs, we analyzed the records of 58 consecutive patients who had been started on the diet. Before using the diet, 80% of the patients had multiple seizure types and 88% were treated with multiple AEDs; these children were among our most intractable patients. Despite this, seizure control improved in 67% of patients with the ketogenic diet, and actuarial analysis indicated that 75% of these improved patients continued the diet for at least 18 months. Sixty-four percent had AEDs reduced, 36% became more alert, and 23% had improved behavior. The improvement in these patients with intractable seizures and the length of time that families maintained the regimen indicate that the ketogenic diet continues to have a very useful therapeutic role in selected patients and their families.